Tiny Trojan horses attack brain cancer cells

November 18, 2010

Scientists in Germany have developed a way of smuggling an anti-cancer drug past the protective blood-brain barrier and into brain tumours and metastases using a nanocarrier  a tiny capsule specially designed to pass through cell membranes and deliver its anti-cancer drug to the cancer cell.

The blood-brain barrier is formed by a network of closely sealed endothelial cells in the brain's capillaries, and it expresses a high level of proteins that pump foreign molecules away from the brain, while allowing others (such as glucose and insulin) that are necessary to the functioning of the brain cells to cross the barrier. This makes it very difficult for molecules, including anti-cancer drugs, to cross the blood-brain barrier and reach tumour cells in the brain. Currently, less than five per cent of drugs are able to cross the barrier and new therapies are needed urgently.

In the research presented today at the 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Berlin, the scientists describe how they designed the nanocarrier with lipid membranes encapsulating and protecting an anti-cancer drug, mitoxantrone, and harnessed it to an existing technology, Angiopep, to get through the blood-brain barrier. Angiopep is a small peptide (amino acid compound) that has been designed to reach brain cells by making use of the receptors on the surface of the blood-brain barrier that are responsible for actively transporting necessary molecules through the barrier to the brain.

The nanocarrier, or Trojan Horse Liposome (THL), has a diameter of between 100-120 nanometres (a nanometre (nm) is one billionth of a metre), equivalent to 1000th the size of a fine grain of sand or 400 time smaller than a human hair. In laboratory membrane experiments, the researchers found that the THL was effective at being taken up by epithelial and glioma cancer cells. Then they tested it on mice with brain metastases from breast tumours and found that the THL was more effective at reducing tumour growth than when mitoxantrone was given on its own (free mitoxantrone). In addition, the THL-treated mice had far fewer side effects, such as gastrointestinal complications, weight loss and dehydration.

Mrs Andrea Orthmann, a PhD student who is working on the project under the supervision of Dr Reiner Zeisig and Dr Iduna Fichter in the Experimental Pharmacology group at the Max-Delbrück Centre for Molecular Medicine, Berlin (Germany), said: "The data show that the THLs are significantly better at reducing tumour growth than the free drug mitoxantrone, or mitoxantrone encapsulated in liposomes without the Angiopep ligand. The THLs reduced the tumour area by 73% in comparison to the untreated control group, and by 45% in comparison to free mitoxantrone. The second important point is the characterisation of side effects. We measured the body weight, blood parameters and the general conditions of the animals. We observed intolerances as a result of the treatment with the free drug (much body weight loss, gastrointestinal disorders, dehydration, pathologic skin and haematology toxicity). All of these side effects were prevented if THLs were used."

The reason why there were fewer side effects with the THL treatment was because the lipid membranes of the THLs protected the anti-cancer drug from affecting or being affected by the rest of the body. "This results in a clear reduction of side effects, which are usually the most serious concerns of anti-cancer drugs," said Mrs Orthmann.

She said that one of the exciting aspects of the research was its potential for use with other drugs and in other cancers and diseases. "Our Trojan Horse Liposomes represent a platform technology that enables the nanocarrier to be loaded easily with different drugs without any chemical modification. In addition, the Angiopep ligand could be replaced by other targeting molecules without too much additional effort. This means that the liposomes have the potential to be used in several other diseases, including neurodegenerative ones such as Alzheimer's, Parkinson's and Huntingdon's disease, as well as other tumours or metastases."

However, there is much work to be carried out first before this technology can enter the clinic. The researchers need to perform more laboratory research to improve the treatment of brain tumours and metastases and to investigate further the mechanism of drug delivery. "Our results demonstrate that the obstacle in the chemotherapeutic treatments of brain tumours and metastases in the brain can be overcome by our Trojan Horse Liposomes which are capable of improved transport through the blood-brain barrier," concluded Mrs Orthmann.

Related Stories

Beset by a host of debilitating and potentially fatal disorders, the human brain is in desperate need of a few good drugs. The catch, however, is that nature has set up a roadblock known as the blood-brain barrier — intended ...

In a study using laboratory animals, researchers found that medications commonly prescribed for erectile dysfunction opened a mechanism called the blood-brain tumor barrier and increased delivery of cancer-fighting drugs ...

(PhysOrg.com) -- The drug vorinostat is able to cross the blood-brain barrier and reduce the development of large metastatic tumors in mice brains by 62 percent when compared to mice that did not receive the drug, according ...

New research by scientists at Cedars-Sinai's Maxine Dunitz Neurosurgical Institute suggests that a drug currently approved to treat erectile dysfunction may significantly enhance the delivery of the anti-cancer drug Herceptin ...

Scientists are reporting the development and successful initial testing of a new form of methotrexate -- the mainstay anticancer drug -- designed to be given as nose drops rather than injected. It shows promise as a more ...

Scientists are reporting development of a long-sought method with the potential for getting medication through a biological barrier that surrounds the brain, where it may limit the brain damage caused by stroke. Their approach ...

Recommended for you

A biomedical breakthrough published today in the journal Nature reveals never-before-seen details of the human body's cellular switchboard that regulates sensory and hormonal responses. The work is based on an X-ray laser ...

(PhysOrg.com) -- The ability to remember the past and imagine the future can significantly affect a person's decisions in life. Scientists refer to the brains ability to think about the past, present, and future as ...

(PhysOrg.com) -- By implanting an electrode into the brain of a person with locked-in syndrome, scientists have demonstrated how to wirelessly transmit neural signals to a speech synthesizer. The "thought-to-speech" process ...

(PhysOrg.com) -- Most people can easily tell the difference between reality and fantasy. We know that characters in novels and movies are fictitious, and we also understand that historical figures - even if we’ve never ...

(PhysOrg.com) -- Humans don’t always make the most rational decisions. As studies have shown, even when logic and reasoning point in one direction, sometimes we chose the opposite route, motivated by personal bias or simply ...

0 comments

Please sign in to add a comment.
Registration is free, and takes less than a minute.
Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.